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  Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 6  |  Page : 96-98
 

Bronchial lavage P16INK4Agene promoter methylation and lung cancer diagnosis: A meta-analysis


Department of Respiratory, The Affiliated Hospital of Hangzhou Normal University, 310015, China

Date of Web Publication24-Dec-2015

Correspondence Address:
R Zhaoyang
Department of Respiratory, The Affiliated Hospital of Hangzhou Normal University, 310015
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.172522

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 » Abstract 

Objective: To evaluate the diagnostic value of bronchial lavage P16INK4A promoter methylation and lung cancer. Materials and Methods: The databases of PubMed, Medline, China National Knowledge Infrastructure, and Wanfang were electronically searched by two reviewers to find the suitable studies related to the association between P16INK4Apromoter methylation and lung cancer. The P16INK4Apromoter methylation rate was extracted from each included individual study. The diagnostic sensitivity, specificity, and area under the receiver operating characteristic ROC curve of bronchial lavage P16INK4Aas a biomarker for diagnosis of lung cancer were pooled by stata11.0 software (Stata Corporation, College Station, TX, USA). Results: At last, 10 publications were included in this meta-analysis. Of the included 10 studies, five are published in English with relatively high quality and other five papers published in Chinese have relatively low quality. The pooled sensitivity and specificity of bronchial lavage P16INK4Apromoter methylation for lung cancer diagnosis were 0.61 (95% confidence interval [CI]: 0.57–0.65) and 0.81 (95% CI: 0.78–0.85), respectively, with random effect model. The ROC curve were calculated and drawn according to Bayes' theorem by stata11.0 software. The systematic area under the ROC was 0.72 (95% CI: 0.68–0.76), which indicated that the diagnostic value of bronchial lavage P16INK4Apromoter methylation for lung cancer was relatively high. Moreover, no significant publication bias was existed in this meta-analysis (t = 0.69, P > 0.05). Conclusion: Bronchial lavage P16INK4A promoter methylation can be a potential biomarker for diagnosis of lung cancer.


Keywords: Bronchial lavage, diagnosis, lung cancer, meta-analysis, methylation


How to cite this article:
Yifan D, Qun L, Yingshuang H, Xulin L, Jianjun W, Qian M, Yuman Y, Zhaoyang R. Bronchial lavage P16INK4Agene promoter methylation and lung cancer diagnosis: A meta-analysis. Indian J Cancer 2015;52, Suppl S2:96-8

How to cite this URL:
Yifan D, Qun L, Yingshuang H, Xulin L, Jianjun W, Qian M, Yuman Y, Zhaoyang R. Bronchial lavage P16INK4Agene promoter methylation and lung cancer diagnosis: A meta-analysis. Indian J Cancer [serial online] 2015 [cited 2019 Nov 13];52, Suppl S2:96-8. Available from: http://www.indianjcancer.com/text.asp?2015/52/6/96/172522



 » Introduction Top


Several studies have reported the tumor suppressor gene promoter hypermethylation in lung cancer, which could be a potential biomarker for lung cancer detection.[1],[2],[3] Kim et al.[4] found that tumor-specific methylation of the p16, RASSF1A, H-cadherin, and RAR beta genes may be a valuable biomarker for the early detection of non-small-cell lung cancer (NSCLC) in bronchial lavage. Moreover, other several studies also reported the potential application value of p16 promoter methylation in bronchial lavage for lung cancer diagnosis.[5],[6] However, the clinical value for the diagnosis of lung cancer of p16 promoter methylation in bronchial lavage was not conclusive. Hence, we performed this meta-analysis to further evaluate its usefulness.


 » Materials and Methods Top


Search method

We searched the PubMed, Medline, China National Knowledge Infrastructure (CNKI), and Wanfang databases to find the open published studies about bronchial lavage P16INK4A gene promoter methylation and lung cancer. The language was limited to English and Chinese. The searching terms were: “P16/INK4A,” “lung cancer,” “lung carcinoma,” and “methylation.”

Data extraction

The related data of each included individual study were extracted by two authors (Dai Yifan and Lv Qun). If disagreement was found, another reviewer was consulted for agreements. The followed information and data were extracted: (1) The publication year of each study (2) the first and corresponding author name; (3) area the study performed; (4) the general characteristics of participants such as age and gender. (5) The gold diagnostic standard; (6) The bronchial lavage P16INK4Amethylation rate in cancer patients and controls; (7) The true positive rate, false positive rate, false negative rate, and true negative rate of each included study.

Quality evaluation

The quality of each included study was evaluated according to Cochrane handbook. The following aspects were assessed for the evaluation of the study quality: (1) Representative spectrum; (2) acceptable reference standard; (3) acceptable delay between tests; (4) partial verification avoided; (5) differential verification avoid; (6) incorporation avoid; (7) reference standard results blinded; (8) index test results blinded; (9) relevant clinical information; (10) uninterpretable results reported; (11) withdrawals explained. All the above aspects were assessed by two reviewers (Huang Yingshuang and Li Xulin), respectively.

Statistical method

The data analysis was done by stata11.0 (Stata Corporation, College Station, TX, USA) and Reviewer Man 5.0 (http://ims.cochrane.org/revman/download). Statistical heterogeneity among the included publications was assessed by Chi-square test,[7] and the inconsistency was calculated by I2.[8] The data were pooled for sensitivity, specificity, and area under the receiver operating characteristic (ROC) by Reviewer Man 5.0. The publication bias was evaluated by linear regression test.


 » Results Top


Main characteristics of the included publications

The databases of PubMed, Medline, CNKI, and Wanfang were electronically searched by two reviewers to find the suitable studies related to the association between P16INK4A promoter methylation and lung cancer. According to the inclusion criteria, we finally included 10 studies related to bronchial lavage P16INK4A promoter methylation and lung cancer. Of the included 10 studies, five are published in English with relatively high quality and other five papers published in Chinese have relatively low quality [Figure 1]. The main characteristics of the 10 publications were demonstrated in [Table 1].
Figure 1: The quality evaluation of the included studies

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Table 1: The main characteristic of the included studies

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Sensitivity and specificity

We use the pathology or cytology as the lung cancer gold diagnosis criteria. The pooled sensitivity and specificity of bronchial lavage P16INK4Apromoter methylation for lung cancer diagnosis were 0.61 (95% confidence interval [CI]: 0.57–0.65) and 0.81 (95% CI: 0.78–0.85), respectively, with random effect model [Figure 2].
Figure 2: The forest plot for bronchial lavage P16INK4A promoter methylation in the diagnosis of lung cancer

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Area under the receiver operating characteristic curve

The ROC curve was calculated and drawn according to Bayes' theorem by stata11.0 software. The systematic area under the ROC (SAUC) was 0.72 (95% CI: 0.68–0.76) [Figure 3], which indicated that the diagnostic value of bronchial lavage P16INK4A promoter methylation for lung cancer was relatively high.
Figure 3: The systematic receiver operating characteristic of bronchial lavage P16INK4A promoter methylation for lung cancer

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Publication bias

The publication bias was evaluated by linear regression test. Moreover, no significant publication bias was existed in this meta-analysis (t = 0.69, P > 0.05) [Figure 4].
Figure 4: The funnel plot for the evaluation of publication bias

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 » Discussion Top


Leading to over 1 million deaths worldwide each year, lung cancer is the most frequent cause of cancer-related worldwide.[17] Recent years, although many new diagnostic techniques have developed, about 80% of the lung cancers were diagnosed at the advanced stages with poor prognosis. It was reported that the overall 5-year survival rates remain below 16% and 6% in NSCLC and small-cell lung cancer, respectively. Hence, early diagnosis of lung cancer is important for its prognostic improvement.

Several studies have found that P16INK4A gene promoter hypermethylation rate in lung cancer patient's bronchial lavage was much higher than that in controls. These results indicated that P 16INK4A promoter hypermethylation detection could be a potential method for lung cancer diagnosis. In our present meta-analysis, we found that the pooled sensitivity and specificity of bronchial lavage P16INK4A promoter methylation for lung cancer diagnosis were 0.61 (95% CI: 0.57–0.65) and 0.81 (95% CI: 0.78–0.85), respectively, with random effect model. The systematic area under the ROC (SAUC) was 0.72 (95% CI: 0.68–0.76), which indicated that the diagnostic value of bronchial lavage P16INK4A promoter methylation for lung cancer was relatively high. For area under the ROC, the best possible prediction method would yield a point in the upper left corner or coordinate of the ROC space, representing 100% sensitivity (no false negatives) and 100% specificity (no false positives). The area under the curve is equal to the probability that a classifier will rank a randomly chosen positive instance higher than a randomly chosen negative one.[18] In our present meta-analysis, the area under the ROC was 0.72 with its 95% confidence interval of 0.68–0.76, indicating a moderate level of accuracy.

In this meta-analysis, we found that the bronchial lavage P16INK4A promoter methylation array had acceptable sensitivity and relatively high specificity in the diagnosis of lung cancer, which could be a useful non-invasive method for lung cancer diagnosis. However, for small subjects, number, and low quality of the included studies, the conclusion should be further confirmed.

 
 » References Top

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Wielscher M, Vierlinger K, Kegler U, Ziesche R, Gsur A, Weinhäusel A. Diagnostic performance of plasma DNA methylation profiles in lung cancer, pulmonary fibrosis and COPD. EBioMedicine 2015;2:927-34.  Back to cited text no. 1
    
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Levine ME, Hosgood HD, Chen B, Absher D, Assimes T. DNA methylation age of blood predicts future onset of lung cancer in the women's health initiative. Aging (Albany NY) 2015;7:690-700.  Back to cited text no. 2
    
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Zhang J, Yu XL, Zheng GF, Zhao F. DAPK promoter methylation status correlates with tumor metastasis and poor prognosis in patients with non-small cell lung cancer. Cancer Biomark 2015;15:609-17.  Back to cited text no. 3
    
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Kim H, Kwon YM, Kim JS, Lee H, Park JH, Shim YM, et al. Tumor-specific methylation in bronchial lavage for the early detection of non-small-cell lung cancer. J Clin Oncol 2004;22:2363-70.  Back to cited text no. 4
    
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Destro A, Bianchi P, Alloisio M, Laghi L, Di Gioia S, Malesci A, et al. K-ras and p16(INK4A) alterations in sputum of NSCLC patients and in heavy asymptomatic chronic smokers. Lung Cancer 2004;44:23-32.  Back to cited text no. 5
    
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Konno S, Morishita Y, Fukasawa M, Shu Y, Wang D, Tanaka R, et al. Anthracotic index and DNA methylation status of sputum contents can be used for identifying the population at risk of lung carcinoma. Cancer 2004;102:348-54.  Back to cited text no. 6
    
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DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.  Back to cited text no. 7
    
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Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.  Back to cited text no. 8
    
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Wang X, Cao A, Peng M, Hu C, Liu D, Gu T, et al. The value of chest CT scan and tumor markers detection in sputum for early diagnosis of peripheral lung cancer. Zhongguo Fei Ai Za Zhi 2004;7:58-63.  Back to cited text no. 9
    
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Georgiou E, Valeri R, Tzimagiorgis G, Anzel J, Krikelis D, Tsilikas C, et al. Aberrant p16 promoter methylation among Greek lung cancer patients and smokers: Correlation with smoking. Eur J Cancer Prev 2007;16:396-402.  Back to cited text no. 10
    
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Liu Y, Lan Q, Shen M, Jin J, Mumford J, Ren D, et al. Aberrant gene promoter methylation in sputum from individuals exposed to smoky coal emissions. Anticancer Res 2008;28:2061-6.  Back to cited text no. 11
    
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Dong J, Sun N, Li J, Liu Z, Zhang B, Chen Z, et al. Development and validation of clinical diagnostic models for the probability of malignancy in solitary pulmonary nodules. Thoracic Cancer 2014;5:162-8.  Back to cited text no. 13
    
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Feng B, Awuti I, Deng Y, Li D, Niyazi M, Aniwar J, et al. Human papillomavirus promotes esophageal squamous cell carcinoma by regulating DNA methylation and expression of HLA-DQB1. Asia-Pacific Journal of Clinical Oncology 2014;10:66–74.  Back to cited text no. 16
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1]



 

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